This Program Project Grant represents the logical progression of the clinical trials and basic research performed during the last Program Project Grant. This new grant contains four projects including a new project, Radioimmunoimaging, defining a focus of the group to include optimally engineered antibodies for cancer imaging. Sanjiv Gambhir, a Nuclear Medicine physician at UCLA who has been instrumental in defining the role of PET in oncology, will head this project. Project 5, Radioimmunotherapy, will continue to define the role of engineered anti-CEA monoclonal antibodies for the treatment of CEA positive malignancies. The major focus will be to define optimal multimodality therapies, combining radio-enhancing chemotherapy with a humanized 9OY-antiCEA antibody. Anti Her2 antibodies are now included in this project. A bioengineered antibody fragment, minibody, will additionally be evaluated as a Radioimmunotherapeutic. Project 6, Radioimmunoimaging, will initiate studies comparing the minibody to a diabody in order to determine the optimal construct for a multicenter trial to be conducted with an 124I-labeled construct compared to 18FDG. This project will involve City of Hope, UCLA, and Memorial Sloan-Kettering Cancer Center. This project will also evaluate a novel prostate antibody specific for prostate stem cell antigen (PSCA). Project 2, Bioengineered Antibodies, will focus on the continued development of optimal antibody constructs for our anti-CEA antibody as well as the introduction of two new antigen targets, Her2 and PSCA. Two immunofusions with gamma-interferon and IL-2 will also be cloned and expressed. Project 1, Radioimmunoconjugates, will focus on the continued development of chelates for Y with focus on cleavable linkers to improve the biodistribution of antibody fragments and the clearance of their radioactivity from the liver and kidney. In addition, efforts will be continued on 64Cu labeled fragments as diagnostic PET imaging agents. 18F chemistry will be explored as the optimal positron-emitting isotope for small antibody fragments. Six cores will continue to support the four projects: Radiophysics, Radiopharmacy, Clinical Production, Analytical and Animal Core, Biostatistics, and Administration. This application takes full advantage of the progress made during the previous applications and our excellent collaborations established over the years.